CREB binding protein (CBP) and p300 are general transcriptional regulators that integrate numerous signal transduction pathways in eukaryotic cells, functioning both as coactivators and repressors of gene expression. They are essential for such basic cellular functions as growth, differentiation, apoptosis, and embryonic development. They also function as tumor suppressors and regulate key genes that control cellular proliferation, tumorigenesis, and cancer progression. Because of their function at the nexus of critical cell signaling networks, CBP and p300 are targeted by many cellular and viral oncoproteins. The goals of the present proposal are to elucidate the structural and molecular basis by which CBP and p300 perform their central regulatory roles to protect against or promote oncogenic transformation. The research will focus on elucidation of the molecular determinants by which CBP and p300 interact with the tumor suppressor p53 and with transforming oncoproteins from human papillomavirus. p53 is activated by a complex phosphorylation cascade that results in enhanced interactions between the p53 transcriptional activation domain and CBP/p300. The E6 and E7 oncoproteins from high risk human papillomavirus recognize and bind CBP/p300 to repress p53-mediated transcriptional pathways, prevent apoptosis, and transform the host cell. State-of-the-art structural, biophysical, and proteomics tools will be utilized to elucidate the molecular basis for key CBP/p300 interactions responsible for activation of the p53 response to DNA damage, immortalization and transformation of the host cell by high risk human papillomavirus strains, and regulation and repression of damage response genes. This research will provide novel insights into the mechanism of activation of p53-regulated genes in response to genotoxic stress, into the molecular interactions through which high risk human papillomavirus oncoproteins subvert the cellular regulatory machinery to immortalize and transform the cell, and into the function of CBP as a transcriptional repressor.